1. Field of the Invention
The present invention relates to 1,4-dihydropyridine derivatives and their use against tumour cells which have acquired resistance to one or more drugs being used as chemotherapeutic agents.
Where chemotherapy is used to treat cancers, the anti-cancer agent being administered, frequently becomes ineffective during treatment, a phenomenon known as `acquired drug resistance`. In some cases this resistance can be to several kinds of anti-cancer agents i.e. a `multidrug resistance`.
It has been shown that the tumour cells which have acquired this multidrug resistance show enhanced excretion of the anti-cancer agents which are being administered as a treatment for the cancer. (T. Tsuruo, Pharmacia Review, No. 23, 115-125 (1987) and Japanese Journal of Cancer Research 79, 285-296 (1988)).
It is not practicable to overcome this problem by simply administering larger doses of the anti-cancer agent(s) as these agents have severe side-effects. Animal tests have suggested that the problem may be overcome by administering the anti-cancer agent(s) in combination with a calcium antagonist, (T. Tsuruo, Pharmacia Review, No. 23, 115-125 (1987)). However, the use of calcium antagonists has not provided a practicable solution to the problem, as the amounts of calcium needed are highly toxic and cause a lowering of blood pressure. Thus, there is a need for therapeutic agents which may help overcome the problems of acquired drug resistance.
Japanese Patent Application Laid Open No. 1-316357 discloses that 1-substituted 1,4-dihydropyridine derivatives may be useful as drugs for overcoming acquired resistance to anti-cancer agents. A series of compounds are disclosed which are free of calcium antagonizing action. However, the compounds are extremely hydrophobic so that their administration would present practical difficulties. The application does not test the effectiveness of the compounds in vivo.
There is a need for drugs useful for overcoming multi-drug resistance but which exhibit low toxicity.